ABSTRACT: A chart on the effects of cannabis derivatives on the immune system, on the respiratory apparatus, on the cardio-circulatory system and on the capacity to drive vehicles.

The "Journal of Psychoactive Drugs" of San Francisco devoted its January-March issue to a monographic review of the latest researches on marijuana. Such researches concern the most controversial arguments on the use of the substance, that is:

a) the effects on the immune system;

b) the effects on the respiratory system;

c) the effects on the cardiovascular system;

d) the effects on the ability to drive vehicles.

A) EFFECTS ON THE IMMUNE SYSTEM

The hypothesis according to which marijuana damages the immune system had been formulated by various authors already in the 70s, through laboratory researches that had been questioned on the basis of the methodology adopted (Cf. Arnao: "Erba proibita", Feltrinelli, 1982, p. 105-107 and 213).

On the Journal of Psychoactive Drugs, the argument was dealt with in two researches, the first conducted by Hollister (Professor of psychiatry and pharmacology at Texas University), the other by Wallace-Tashkin-Oishi-Barbers (in a researched financed by the National Institute of Drug Abuse).

HOLLISTER RESEARCH - The effects on the immune function are measured on the basis of four parameters: mediated cellular immunity, bio-humoral mechanisms, cellular defense and immunogenetic activity.

The author reaches the following conclusions:

"In spite of the rather vast literature produced in the last 15 years, an effect of cannabinoids on the immune system still remains to be proved. The evidence is contradictory, because a certain level of immunosuppressive activity has been certified only with in-vitro experiments, which are altered by the extremely high dosage used, and by the lack of comparisons with possible effects similar of other substances. The closer the experimental investigations came to the real clinical situations, the less convincing was the evidence of an immunosuppressive effect" (Hollister: "Marijuana and Immunity", in "Journal of Psychoactive Drugs", vol. 20/1, Jan-Mar 1988, p. 7).

On the other hand, the researchers'' interest, which had been very active in the 70s, vanished in the 80s. A thing that would prove, according to the author, that further studies on this topic will supposedly not yield interesting results.

As regards the relation between the use of cannabis and AIDS, the author writes that "there is no clinical evidence or epidemiological result that proves the existence of a link between the use of marijuana on the one hand and Hiv contagion or the development of Aids on the other" (op. cit. p.5).

For hiv-affected subjects as well there is no evidence that the use of marijuana or alcohol increases the risk of contracting AIDS (op. cit. p.7).

WALLACE, TASHKIN OISHI AND BARBERS RESEARCH - In this research the effects of marijuana are compared with those of tobacco. The immune function is evaluated analysing the lymphocytic activity. Three categories of subjects have been considered:

NS: non smokers

TS: smokers of only tobacco, average consumption a packet a day for 24 years

MS: smokers of marijuana (in doses similar to the previous group) and tobacco (a packet a day for at least 16 years).

The research proved that the use of marijuana, unlike that of tobacco, has no inhibitory action on the immune response. This difference is explained by the authors with various hypotheses:

a) that marijuana does not contain the immunosuppressive agents contained in tobacco;

b) that marijuana contains factors that contrast the immunosuppressive activity;

c) that the difference in the response depends from the dosage, which, though corresponding to the most diffused modality of use, is higher for tobacco than for marijuana.

This means that dosages of marijuana equivalent to those adopted by the researchers do not cause any immunosuppressive activity.

B) EFFECTS ON THE RESPIRATORY APPARATUS

The effects on the respiratory apparatus have been investigated in the Tashkin-Simmons-Clark researches (UCLA University), and in the Fligiel-Venkat-Gong-Tashkin researches (financed by the NIDA).

THE TASHKIN, SIMMONS, CLARK RESEARCH - This research investigated bronchial hyperreactivity (symptom of a disorder of the respiratory apparatus and factor of risk for the appearance of an obstructive chronic disease) comparatively in three groups of subjects:

1) MS: marijuana smokers in doses equivalent to 3,3 joints a day for 20 years;

2) TS: smokers of tobacco in doses equivalent to 1,14 packets a day for 20 years;

3) MTS: smokers of tobacco (0,76 packets a day for 20 years) and marijuana (2,6 joints a day for 20 years).

Bronchial hyperreactivity was remarked only in the MTS group. In practice, this means that this type of risks is not brought about with levels of use equivalent to the one indicated. There is however an increase of hyperreactivity if tobacco and marijuana are used jointly, even in doses inferior to those that result harmless if the substances are used separately (Tashkin and others: "Effects of Habitual Smoking of Marijuana Alone and with Tobacco on Nonspecific Airways Hyperreactivity", in: op.cit. p. 21-25).

FLIGIEL, VENKAT, GONG, TASHKIN RESEARCH - through a series of hystological analyses, this research investigated the bronchial pathology of three groups of subjects:

MS: marijuana consumers who have smoked at least a joint in the last month and an average of one joint a day for at least three years in the past;

TS: subjects who have smoked at least a cigarette a day for over a year;

MTS: subjects who have smoked marijuana and tobacco.

From the global analysis of the research, the authors reach the conclusion that "smoking marijuana can be equally if not more harmful than tobacco smoking for the respiratory epithelium" (p. 41). The maximum level of toxicity was found in the MTS group.

From the dosage analyzed in the research, there clearly emerges that the comparison between marijuana and tobacco must be done considering equal amounts of substance smoked, and not at the most common levels of consumption of the relative substances. From a practical point of view, this research proves that marijuana smoking damages the respiratory epithelium to an equal if not higher degree to that determined by equivalent quantities of tobacco smoking. On the other hand, the authors state that the potentiality of these alterations as factors of risk in developing a chronic disease or lung cancer is still unknown, albeit not impossible (Fligiel et al: "Bronchial Pathology in Chronic Marijuana Smokers" in op.cit. p. 33-42).

C) EFFECTS ON THE CARDIOVASCULAR SYSTEM

TASHKIN, WU, DJAHED RESEARCH - The development of carbon oxide (CO) is one of the collateral effects of combustion, and is one of the components of substances that are smoked. On contact with blood, CO binds itself to hemoglobin, forming carboxyhemoglobin (COhb), which is a relevant factor of risk for coronary disease.

The research evaluated the incidence of this risk measuring the levels of COhb in tobacco and marijuana smokers; the acute effects (immediate and transitory increase of COhb directly caused by the single dose) and the chronic effects (permanent increase caused by the accumulation of the doses) were analyzed separately.

Three groups of subjects were analysed:

MS (n.115): smokers of marijuana only, in doses equivalent to 2,8 joints a day;

TS (n.52): smokers of tobacco in doses equivalent to one packet a day;

MTS (n.104): smokers of marijuana and tobacco (2,7 joints and 13 cigarettes a day).

It was established that the acute effect for the MS group was four times superior to that of the TS group. According to the authors, this is due to the fact that marijuana is inhaled more deeply and for a longer time than tobacco. On the other hand, because one of the effects of THC is that of causing an increase in the frequency of pulsations, this means an increase of the risk of an acute crisis for those who have a pre-existing situation of disorder of the coronary arteries.

The chronic effects are instead inferior for the MS group, whose level of COhb is inferior than that of the TS and MTS groups. According to the authors, this is basically due to the difference in the doses: the TS group, unlike the MS group, smoke at too short intervals to allow a disposal of the COhn. From a practical point of view, this determines a higher level of chronic, that is, permanent, risk in the TS and MS groups.

The frequency and the deepness of inhalation and the lapse of time in which the smoke is withheld in the lungs are therefore the relevant factors of the risk of an increase of COhb due to the marijuana smoked. The risk is independent of the pharmacological potency, that is, from the rate of THC, but is related to the quantity of substance smoked.

The possibility of increasing the COHb appears to be the only risk, from a practical point of view, to have been proved of the use of smoked cannabis, limited to subjects affected by coronary pathology.

From the context of the research it can be gathered that such risk could be reduced (a) by limiting the quantity of substance smoked (for example avoid smoking marijuana together with tobacco) and (b) smoking with a technique that subdues the impact of the smoke on the pulmonary absorption (Tashkin et al: "Acute and Chronic Effects of Marijuana Smoking Compared with Tobacco Smoking on Blood Carboxyemoglobin Levels" in op.cit. p. 27-31).

D) EFFECTS ON AUTOMOBILE DRIVING

To what extent does the use of cannabis affect the ability to drive? Until 1982, few researches had thoroughly investigated the problem (Cf. Arnao 1982, p. 93-98 and p. 220).

A research conducted by Gieringer attempted to probe the question more deeply, critically analysing all the researches conducted to that moment.

The author begins with a short review of laboratory researches. Studies conducted with the aid of a simulator generally found a reduction of the driving ability, but also a tendency to reduce the speed and avoid dangerous behaviours; unlike alcohol, which, as we all know, induces to drive faster and in a dangerous way. Another relevant difference lies in the reaction time, which increases with alcohol and remains unaltered with cannabis.

These data are confirmed in a research conducted by Hansteen - Miller - Lonero - Reid, in which 38 subjects, administered different doses of cannabis and alcohol, were submitted to driving tests on real automobiles on pre-established routes. The result was that a dosage of 5,9 - 6,8 mg. of THC (the equivalent of one 600-700 mg. joint containing 1% of marijuana) globally determines a reduction of the capacity to drive inferior to a dosage of alcohol corresponding to an alcohol rate of 0,07% (two glasses of wine), below the limit (0.08) tolerated by the laws of the Western countries (Cf. Hansteen et al: "Effects of Cannabis and Alcohol on Automobile Driving and Psychomotor Tracking" in Dornbush - Freedman - Fink [Edited by]: "Chronic Cannabis Use", New York Academy of Science, 1976).

Gieringer then examines a series of researches based on the search for metabolites of cannabis and of other drugs in the blood in cases of road accidents.

Between 1978 and 1981, Mason - McBay carried out a research in North Carolina on 600 so-called "one car" road accident victims (that is, involving one vehicle, and therefore occurred due to the prevailing responsibility of the person driving).

The blood test gave the following results:

- THC in blood levels higher than 3mg/ml in 7,8% of cases, of which 5,3% (on the total of cases) also had alcohol levels higher than 1,10%;

- alcohol present in the blood in 79,3% of cases;

- methaqualone present in 6,2%, barbiturates in 3% of cases.

A research conducted in Cimbura, Ontario, on 1169 subjects (drivers or pedestrians) involved in lethal accidents between 1982 and 1984 yielded the following results:

- in 10,9% of subjects the presence in the blood of THC at levels superior ro 1mg/ml; among these in 7,4% (on the total cases) there was a level of alcohol higher than 0,08%; - in 57,1% alcohol present in the blood.

A research conducted by Williams et al on 440 drivers (aged 25-34) died in road accidents in California between 1982 and 1983 gave the following results:

- THC at levels of 0,2-0,9mg/ml in 14% of cases;

- THC between 1 and 1,9 mg/ml in 8%;

- THC between 2 and 4,9 mg/ml in 9,6%;

- THC 5mg/ml or more in 5,2%.

- among subjects tested positive for THC (a total of 37%), 25% (on the total) had an alcohol level higher than 0,10%, 5% a level of alcohol inferior to 0,10% and in 7% (on the total) presence of other drugs in the body;

- only alcohol in 70% of cases;

- only cocaine in 11% of cases.

These figures must be interpreted considering some parameters of evaluation.

As far as alcohol is concerned, the main part of road accidents occurs with levels of alcohol between 0,08% and 0,10% (Cf. Canadian Government Commission of Inquiry: "Final Report", p. 394), and these levels must therefore be considered indicative of an alteration of the driving capacity.

The levels of THC in the blood range from values of about 50mg/ml immediately after the assumption, remain at 10mg approximately during the second hour to drop below 1mg/ml after three or four hours (Cf. King - Teale - Marks: "Biochemical aspects of cannabis" in Graham [edited by]: Hashish and Marijuana", Newton Compton 1979, p. 109, and Morgan: "Marijuana Metabolism in the Context of Urine Testing for Cannabinoid Metabolite" in Journal of Psychoactive Drugs, vol. 20/1, 1988, p. 108-109). Because the period of psychoactive effect of cannabis is generally considered to be not superior to three hours (Cf. Weil - Zinberg - Nielsen: "Clinical and Psychological Effects of Marijuana in Man" in Grupp [edited by]: "Marijuana", Merril 1971, p.164), it can be reasonably established that levels inferior to 3mg/ml correspond to a very light state of intoxication: this would among other things explain why Mason's research considered only levels superior to 3mg/ml as possible causes of accidents. Moreover, Gieringer point

s out that levels of THC up to 2,5mg/ml can be remarked even many hours after the assumption, and therefore do not prove a state of intoxication.

On the other hand, marijuana intoxication is not necessarily the cause of the accidents. The research conducted by Williams tried to explain this fundamental thing, by using a series of parameters that quantified the responsibility of the subjects in the dynamics of the accident. The "index of responsibility" was thus evaluated:

- the drivers who were under the effect of alcohol and other drugs were responsible in 95% of cases;

- drivers under the effect of alcohol in 92% of cases;

- drivers who had never made use of drugs in 71% of cases;

- drivers under the effect of marijuana in 53% of cases;

These figures allow us to conclude that marijuana intoxication was a factor of risk with an incidence inferior to the cases in which the subjects were not under the effect of drugs. From a global evaluation of the researches by him examined, Gieringer judges that in 8-11% of cases of mortality there was a level of THC that pointed to an effective state of intoxication, that is superior to 2,0-3.0mg/ml, but that only in 2,8-4,8% of cases a level superior to 5 mg/ml, pointing to an effective and considerable alteration of the capacities.

On the other hand, the fact that from 81 to 87% of subjects who tested THC positive were also positive for alcohol, brings the incidence of the cases in which only THC was present to values of 1,8% for levels that point to an intoxication and 0,54% for levels higher than 5mg/ml. This brings the author to believe that the main part of the accidents of THC positive subjects do not depend on cannabis but from alcohol, and to conclude that:

"marijuana in itself seems to be a minor or irrelevant factor of risk in mortal accidents (...) It is not likely that the elimination of marijuana can have a favourable impact on public security until consumers continue to use other drugs, and especially alcohol (...). In consideration of this, it is ironic that the current technology of research of drugs in urine reflects the opposite prejudice, being there an extreme intolerance with marijuana but not with alcohol (...). The diffusion of tests on marijuana seems to be based on deep social and political prejudices more than on an effective scientific evidence". (p.100).

CANNABIS AND VIOLENCE

CANNABIS PHARMACOLOGY

Refer to Drug Policy 1989-1990 p. 352-353)

LETHAL DOSE: See Drug Policy 1989-1990 p. 352-353. Refer also to Grinspoon "Marijuana reconsidered" p. 252-253

The lethal dose is 20-40 Kg.

SECURITY FACTOR (EFFECTIVE DOSE/LETHAL DOSE RATIO):

ALCOHOL-CANNABIS COMPARISON

For cannabis it is 1/20,000 - 1/40,000

ALCOHOL: EFFECTIVE DOSE BLOOD CONCENTRATION 0,05-0,10%

LETHAL DOSE 0,4-0,5%

SECURITY FACTOR = from 4 to 10

(SOURCE: Mikuriya on "New Physician" 1969)

lethal dose according to Milam-Ketcham:

0,3 minimum lethal dose / 0,4 average dose for coma / 0,5 average dose for negative effects on the heart and respiratory function / 0,6 lethal dose for the majority of cases

level 0,2 corresponds to the assumption of 8 cans of beer on the part of a male subjects weighing 68 Kg

(Milam-Ketcham: "Under the influence" 1981 books n. 415)

U.S. FIGURES ON MORTALITY AND EMERGENCY HOSPITALIZATIONS FOR CANNABIS

1982 DAWN 199,000 cases in the U.S.

cases of emergency hospitalizations

5295 of which only 22% not associated to other substances (1164)

(NIDA RM 61, p.18)

1985 DAWN

cases of death with "mention" of cannabis alone; 1, versus 29 for aspirin and 48 for tranquillizers

(NIDA: Annual data 1985, p. 58 and 64 n. 628)

emergency hospitalizations 1338 cases for cannabis alone, versus 5451 cases for tranquillizers and 26889 for aspirin

1987 DAWN

cases of death related to cannabis alone: 0 versus 30 for aspirin and 11 for tranquillizers

hospitalizations: 1744 cases for cannabis alone, versus 2627 for aspirin

(NIDA: Annual Data 1987)